Current Research Provides Insight into the Biological Basis and Diagnostic Potential for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe fatigue illness that occurs most commonly following a viral infection, but other physiological triggers are also implicated. It has a profound long-term impact on the life of the affected person. ME/CFS is diagnosed primarily by the exclusion of other fatigue illnesses, but the availability of multiple case definitions for ME/CFS has complicated diagnosis for clinicians. There has been ongoing controversy over the nature of ME/CFS, but a recent detailed report from the Institute of Medicine (Academy of Sciences, USA) concluded that ME/CFS is a medical, not psychiatric illness. Importantly, aspects of the biological basis of the ongoing disease have been revealed over the last 2-3 years that promise new leads towards an effective clinical diagnostic test that may have a general application. Our detailed molecular studies with a preclinical study of ME/CFS patients, along with the complementary research of others, have reported an elevation of inflammatory and immune processes, ongoing neuro-inflammation, and decreases in general metabolism and mitochondrial function for energy production in ME/CFS, which contribute to the ongoing remitting/relapsing etiology of the illness. These biological changes have generated potential molecular biomarkers for use in diagnostic ME/CFS testing.

Keywords: chronic fatigue syndrome; circadian rhythm; diagnostic biomarker; inflammation and immunity; metabolism; mitochondria; myalgic encephalomyelitis; neuro-inflammation.

Figure 1

Scatter plot of RT-qPCR assay Ct values (defined below) for IL8, NFKBIA, and TNFAIP3. Each peripheral blood mononuclear cell (PBMC) sample (myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) n = 10, control n = 10) was measured in triplicate, with the mean Ct value for each gene in both ME/CFS and control cohorts shown (orange line). A Ct value is the Reverse Transcription quantitative Polymerase Chain Reaction (RT-qPCR) amplification cycle at which the gene transcript copy number exceeded the individually calculated baseline threshold level for that gene. Figure taken from our own recently published study [49]. Red bars indicate the mean Ct value in each case. Statistical significance (p < 0.05) between the two groups is indicated by the *.

Figure 2

Box-and-whisker plots of ME/CFS and control phosphorylated PKR/protein kinase RNA-activated (pPKR:PKR) ratios in PBMCs and neutrophils. In-house affinity purified antibodies against phosphorylated PKR (active form) and PKR (inactive form) were used to detect the ratio of pPKR:PKR in isolated PBMCs and neutrophils from a matched patient/control ME/CFS study. The median pPKR:PKR ratio is shown, and the interquartile range, maximum and minimum ratio values. Outliers are indicated with a (*). A t-test between ME/CFS and controls gave a P-value of 0.057 in PBMCs (ME/CFS n = 9, controls n = 9) and 0.142 in Neutrophils (ME/CFS n = 9, controls n = 10). This figure has been constructed by author ES from data referenced in her PhD thesis, with permission to publish from University of Otago [38].